Project Summary: Chronic pain is a significant public health burden for which there are few effective treatments; individuals with chronic pain are a central component to the current opioid epidemic. Delta-9- tetrahydrocannabinol (THC), the primary psychoactive chemical of cannabis, holds promise as a therapeutic candidate to treat chronic pain. However, analgesia is accompanied by intoxication and abuse liability, thus limiting its clinical utility. Terpenes are organic compounds that contribute to the aromatic nature and flavor of cannabis; it has been hypothesized that these compounds may interact synergistically with THC to enhance its therapeutic effects with reduced adverse consequences. As such, terpenes may increase the analgesic effects of low, minimally intoxicating, doses of THC, and/or reduce adverse consequences of higher THC doses. Preclinical research demonstrates that the terpenes myrcene and -caryophyllene (BCP) elicit antinociceptive effects and have opioid-sparing properties. These effects are, in part, mediated by the mu-opioid receptor. It is unknown if these findings translate to humans. Understanding if these terpenes have analgesic properties alone, or in combination with THC, is fundamental to developing novel cannabinoid-based therapeutics to treat pain. In addition, investigating adverse effects of these terpenes (abuse liability, intoxication) will clarify their clinical potential. At a time when pharmacotherapeutic strategies to decrease reliance on opioids for pain relief are desperately needed, probing the 1) analgesic effects, 2) potential THC- and opioid-sparing properties, and 3) mechanism of these terpenes is of significant interest. The proposed double-blind, placebo-controlled studies will be the first to rigorously assess the dose-dependent analgesic effects of ecologically-relevant doses of myrcene and BCP and determine their THC- and opioid-sparing effects. Study findings will be essential in understanding the clinical potential of terpenes alone and in conjunction with THC for pain management. The proposed double-blind, placebo-controlled, within-subject studies in recreational cannabis smokers (N=30, 15M, 15F in each study) will first ascertain the dose-dependent analgesic potential of vaporized myrcene and BCP alone and in combination with sub-analgesic (5 mg) and analgesic (15 mg) doses of THC (Specific Aim 1). The myrcene/THC and BCP/THC dose combinations that produce the greatest analgesia and minimal intoxication and abuse liability will then be tested for their opioid sparing effects (Specific Aim 2). Opioid modulation of combined terpene/THC analgesia will be assessed with co-administration of naltrexone, an opioid antagonist (Specific Aim 2). Findings from these studies address a significant public health priority by investigating terpenes as a safe, well tolerated novel pharmacotherapeutic strategy to manage pain. This is an urgent area of research as alternatives to opioids and strategies to decrease use of high opioid doses are desperately needed.